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Cited by 47Connective Tissue Growth Factor ResearchProtein Kinase Regulation and GTPase SignalingCell Adhesion Molecules Research

Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine‐rich protein 61

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Walsh, Colin T., Radeff‐Huang, Julie, Matteo, Rosalia, Hsiao, Albert, Subramaniam, Shankar, Stupack, Dwayne, Brown, Joan Heller·2008·The FASEB Journal
DOI 10.1096/fj.08-113266PMC PMC3980657
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Abstract

A subset of G‐protein coupled receptors (GPCRs), including the thrombin receptor (PARI), elicits mitogenic responses. Thrombin also activates Ras homolog gene family member A (RhoA) and activating protein (AP‐1) ‐mediated gene expression in 1321N1 astrocytoma cells, whereas the nonmitogenic agonist carbachol does not. Transcriptomic analysis was used to explore differential gene induction by these agonists and revealed that the matricellular protein cysteine‐rich 61 (Cyr61/CCN1) is selectively induced by thrombin. The ability of GPCR agonists to induce Cyr61 parallels their ability to activate RhoA;agonist‐stimulated Cyr61 expression is inhibited by C3 toxin. When Cyr61 is down‐regulated using short interfering RNA (siRNA) or short‐hairpin RNA (shRNA), thrombin‐induced DNA synthesis is significantly attenuated. When Cyr61 expression is induced, it appears in the extracellular compartment and on the cell surface. Extracellular Cyr61 interacts with α 5 , α 6 , and β 1 integrins on these cells, and monoclonal antibodies directed against α 5 and β 1 integrins inhibit thrombin‐induced DNA synthesis. Functional blockade of Cyr61 with soluble heparin or anti‐Cyr61 antibodies also inhibits thrombin‐induced DNA synthesis. Thus Cyr61 is a highly inducible, secreted extracellular factor through which GPCR and RhoA signaling pathways engage integrins that contribute to GPCR‐mediated proliferation.— Walsh, C. T., Radeff‐Huang, J., Matteo, R., Hsiao, A., Subramaniam, S., Stupack, D., and Brown, J. H. Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine‐rich protein 61. FASEB J. 22, 4011–4021 (2008)

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  • Thrombin acts through GPCR and RhoA signaling to induce CCN1, which then interacts with integrins to promote cell proliferation, connecting GPCR and integrin signaling to enhance thrombin-induced cell proliferation.

    “Thrombin acts through the GPCR and RhoA signaling pathways to induce CCN1, which in turn interacts with integrins to promote cell proliferation [35]. Thus, CCN1 serves to connect the GPCR and integrin signaling pathways to enhance thrombin-induced cell proliferation [38].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [35]

  • CCN1 is activated by agonists of G protein-coupled receptors such as thrombin, prostaglandins E2 and F2α, and sphingosine-1-phosphate.

    “CCN1 is activated by agonists of G protein-coupled receptors (GPCRs) such as thrombin [34,35], prostaglandins E2 and F2α [33,36], and sphinogosine-1-phosphate [37].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [35]

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Research works printed but not linked: 2

  1. Lau L. F., Lam S. C. T. Integrated-mediated CCN functions. Perbal B., Takigawa M., editors. Imperial College Press; London, UK: CCN Proteins: A New Family of Cell Growth and Differentiation Regulators. 2005:61–79. [Google Scholar]
  2. Seuwen K., Kahan C., Hartmann T., Pouyssegur J. Strong and persistent activation of inositol lipid breakdown induces early mitogenic events but not Go to S phase progression in hamster fibroblasts. J Biol Chem. 1990;265:22292–22299. [PubMed] [Google Scholar]

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Authors
Walsh, C. T., Radeff‐Huang, J., Matteo, R., Hsiao, A., Subramaniam, S., Stupack, D., & Brown, J. H.
Affiliations
  • University of California San Diego (US)
  • Department of Pharmacology University of California San Diego La Jolla California USA
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2008-08-07
Volume
22
Issue
11
Pages
4011-4021
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.08-113266
PMC
PMC3980657
OpenAlex
W2108337464
Cited by
47
References
78
Citations by year
2025: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2020: 1 · 2019: 3 · 2018: 6 · 2017: 2 · 2015: 6 · 2014: 4 · 2013: 5 · 2012: 4
FWCI
1.10
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01CA218859)
  • National Institute of General Medical Sciences (R01GM036927)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
protease-activated receptor 1, PAR1, RhoA, CYR61, integrins, integrin alpha5, CD49f, beta1 integrin, cell proliferation, G protein-coupled receptors, astrocytoma cells, mitogenic signaling, matricellular proteins, heparin
MeSH terms
Carbachol, Cardiotonic Agents, Fibrinolytic Agents, Heparin, Humans, Platelet Aggregation Inhibitors, Signal Transduction, Down-Regulation, Integrins, Immediate-Early Proteins, Transcription Factor AP-1, rhoA GTP-Binding Protein, RNA, Small Interfering, Intercellular Signaling Peptides and Proteins, Receptor, PAR-1, Cell Line, Tumor, Cell Proliferation, Cysteine-Rich Protein 61

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